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阿尔茨海默病的丝的冷EM结构
Anthony W P Fitzpatrick1, Benjamin Falcon1, Shaoda He1
1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
Nature
|July 6, 2017
概括
研究人员已经确定了阿尔茨海默病大脑中的状和直状丝的原子结构. 这些结构揭示了聚的核心播种机制,对于理解神经退行性疾病至关重要.
科学领域:
- 神经科学
- 结构生物学
- 生物化学
背景情况:
- 阿尔茨海默病是最常见的神经退行性疾病,缺乏基于机制的治疗方法.
- 这种疾病的特征是神经纤维损伤和神经质斑块,主要由丝组成.
- 对于了解疾病机制至关重要的高分辨率丝结构以前是不可用的.
研究的目的:
- 确定阿尔茨海默病患者大脑中的状和直状丝的高分辨率原子结构.
- 阐明tau聚合的结构基础,并确定核心播种机制.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 来生成高分辨率图 (3.4-3.5 Å) 的丝.
- 原子模型是基于对联螺旋和直线丝的冷EM数据构建的.
- 进行了丝芯和原丝结构的分析.
主要成果:
- 成功确定了阿尔茨海默病大脑中的状和直状丝的原子模型.
- 芯由两个相同的原 (tau蛋白的306-378残留物) 组成,具有交叉β/β螺旋结构.
- 偶联的螺旋和直线纤维被确定为超结构的多态体,在原纤维间的包装上有所不同.
结论:
- 可直接从患者获得的材料中对粉样纤维进行原子级别的鉴定.
- 确定的结构为阿尔茨海默病中聚的播种机制提供了洞察力.
- 这项工作为研究病症和开发向治疗铺平了道路.
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